A next generation mathematical model for the in vitro to clinical translation of T-cell engagers.
Avidity
Bispecific
Blinatumomab
Chi factor
Mathematical model
QSP
T-cell engager
Journal
Journal of pharmacokinetics and pharmacodynamics
ISSN: 1573-8744
Titre abrégé: J Pharmacokinet Pharmacodyn
Pays: United States
ID NLM: 101096520
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
06
10
2022
accepted:
01
02
2023
medline:
11
5
2023
pubmed:
16
2
2023
entrez:
15
2
2023
Statut:
ppublish
Résumé
T-cell engager (TCE) molecules activate the immune system and direct it to kill tumor cells. The key mechanism of action of TCEs is to crosslink CD3 on T cells and tumor associated antigens (TAAs) on tumor cells. The formation of this trimolecular complex (i.e. trimer) mimics the immune synapse, leading to therapeutic-dependent T-cell activation and killing of tumor cells. Computational models supporting TCE development must predict trimer formation accurately. Here, we present a next-generation two-step binding mathematical model for TCEs to describe trimer formation. Specifically, we propose to model the second binding step with trans-avidity and as a two-dimensional (2D) process where the reactants are modeled as the cell-surface density. Compared to the 3D binding model where the reactants are described in terms of concentration, the 2D model predicts less sensitivity of trimer formation to varying cell densities, which better matches changes in EC
Identifiants
pubmed: 36790614
doi: 10.1007/s10928-023-09846-y
pii: 10.1007/s10928-023-09846-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
215-227Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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